How It Works
Bottom Line: D-limonene has not been shown to be an effective cancer treatment in humans.
D-limonene is made from the peels of citrus fruits. Scientists are not exactly sure how it works, but it showed some anticancer activity in laboratory studies. These studies suggest that D-limonene alters the signaling pathways within cancer cells in a way that stops cancer cells from multiplying and causes their death (this is called "apoptosis"). In animals, D-limonene slowed the growth of pancreatic, stomach, colon, skin, and liver cancers. It also slowed formation of tumors and their progression in animals exposed to cancer-causing substances. However, these anticancer effects have not been shown in humans.
Purported Uses
To prevent and treat cancer
Although test tube and animal studies show that D-limonene has anti-cancer activity, this effect was not found in early clinical trials.
Research Evidence
Cancer treatment:
Researchers conducted a two-part study to assess the effectiveness of D-limonene in treating solid tumors that had not responded to other therapies. In the first part, 32 patients with solid tumors received a range of doses of intravenous D-limonene in order to identify how high the doses could go without causing toxic side effects. Because one breast cancer patient showed a partial response (shrinkage of her tumor), ten additional breast cancer patients were added to the study and were given 8 g/m2/day of D-limonene. However, none of these patients showed any tumor shrinkage. This small study does not support d-limonene as a cancer treatment.
Warnings
This product is regulated by the F.D.A. as a dietary supplement. Unlike approved drugs, supplements are not required to be manufactured under specific standardized conditions. This product may not contain the labeled amount or may be contaminated. In addition, it may not have been tested for safety or effectiveness.
Side Effects
Nausea
Vomiting
Diarrhea
Allergic skin rash
Scientific Name
p-mentha-1,8-diene
Common Name
R-limonene, orange peel oil, citrus peel oil, citrene
Clinical Summary
Derived from the peels of citrus fruits, D-limonene is used by patients to prevent and treat cancer. Following oral administration, D-limonene is rapidly metabolized to limonene-1,2-diol, perillic acid, dihydroperillic acid, and uroterpenol
(1) (2) (3).
An epidemiological study reported an inverse relationship between citrus peel consumption and squamous cell carcinoma
(4). In vitro and animal studies suggest that D-limonene has anticancer effects, but an early clinical trial in breast cancer patients failed to support the observations
(5) (6). Further research is necessary to determine if D-limonene has a role in the prevention or treatment of cancer.
Side effects of D-limonene include nausea, vomiting, and diarrhea
(3), and a few cases of contact dermatitis and asthma have also been reported
(7) (8).
Purported uses
Cancer prevention
Cancer treatment
Constituents
Monocyclic monoterpene
Mechanism of Action
Although the exact mechanism of action is unknown, D-Limonene and its metabolites, perillic acid, dihydroperillic acid, uroterpenol, and limonene1,2-diol, may inhibit tumor growth via inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway
(9) (10). D-Limonene metabolites also cause G1 cell cycle arrest, inhibit posttranslational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes
(6). Animal studies show activity of D-limonene against pancreatic, stomach, colon, skin, and liver cancers
(5). Data also indicate that D-limonene slows the promotion/progression stage of carcinogen-induced tumors in rats
(11) (12).
Pharmacokinetics
Following oral administration, D-limonene is absorbed rapidly and metabolized to perillic acid (PA), dihydroperillic acid (DPA), limonene1,2-diol, and uroterpenol. D-Limonene metabolites distribute throughout the body to all sites, including adipose tissue, and are eliminated as glucuronide metabolites in the urine
(1) (2) (3).
Adverse Reactions
Reported: Nausea, vomiting, diarrhea (3)
Case Report: Contact Dermatitis (7) and asthma (8)
Herb-Drug Interactions
None known
Literature Summary and Critique
References
- Crowell PL, et al. Human metabolism of the experimental cancer therapeutic agent d-limonene. Cancer Chemother Pharmacol 1994;35:31-7.
- Hardcastle IR, et al. Inhibition of protein prenylation by metabolites of limonene. Biochem Pharmacol 1999;57:801-9.
- Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Chemother Pharmacol 1998;42:111-7.
- Hakim IA, Harris RB, Ritenbaugh C. Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin. Nutr Cancer. 2000;37(2):161-168.
- Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev 1998;3:448-57.
- Reddy BS, et al. Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 1997;57:420-5.
- Topham EJ, Wakelin SH. D-Limonene contact dermatitis from hand cleansers. Contact Dermatitis. 2003 Aug;49(2):108-9.
- Guarneri F, Barbuzza O, Vaccaro M, et al. Allergic contact dermatitis and asthma caused by limonene in a labourer handling citrus fruits. Contact Dermatitis. May 2008;58(5):315-316.
- Hudes GR, et al. Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 2000;6:3071-80.
- Kaji I, et al. Inhibition by d-limonene of experimental hepatocarcinogenesis in Sprague-Dawley rats does not involve p21(ras) plasma membrane association. Int J Cancer 2001;93:441-4.
- Asamoto M, et al. Mammary carcinomas induced in human c-Ha-ras proto-oncogene transgenic rats are estrogen-independent, but responsive to d-limonene treatment. Jpn J Cancer Res 2002;93:32-5.
- Uedo N, et al. Inhibition by d-limonene of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats. Cancer Lett 1999;137:131-6.
